Coronary artery disease (CAD) is a disease that affects the blood vessels that nourish the heart muscle. CAD is a result of atherosclerosis, a build-up of fatty substances on the inner walls of the coronary arteries. When the coronary arteries become clogged or narrowed by these waxy “fats”, blood flow is restricted and the heart muscle does not receive adequate oxygen, which can lead to heart attack and even death. In many cases, angina pectoris (chest pain) may occur when the heart is not receiving enough oxygen. The risk of CAD increases with elevated levels of total cholesterol and low-density lipoprotein (LDL) in the blood, but decreases when high-density lipoprotein (HDL) increases. In the United States, cardiovascular diseases are the leading cause of death in both genders, accounting for about one-third of deaths each year; the American Heart Association estimates that more than 12 million people have some form of CAD history. (American Heart Association, Fighting Heart Disease and Stroke, 2000, Heart and Stroke Statistical Update, p.5)
The problem of atherosclerosis may extend beyond the heart. Patients with CAD may also have atherosclerosis of the arterial beds including peripheral artery occlusive disease (PAOD), renal artery stenosis (RAS) and cerebrovascular disease (CBVD). This comorbidity results in an increased risk for stroke, myorcardial infarction (MI), cardiovascular death, and renal failure.
Vessels that are narrowed due to atherosclerosis are said to have undergone stenosis. The term “restenosis” refers to a re-narrowing of a vessel after a procedure has been performed to reduce a previous narrowing.
Percutaneous transluminal coronary angioplasty (PTCA) is the procedure generally used to open an obstructed artery. The placement of a balloon expanded stent or a self-expandable stent during PTCA is the leading minimally invasive treatment option. Stents are used in the treatment of new lesions or blockages, and in areas where restenosis has occurred.
A major limitation of PTCA is the problem of post-PTCA closure of the vessel, both immediately after PTCA (acute occlusion) and in the long term (restenosis). Restenosis after angioplasty is a more gradual process and involves initial formation of a subcritical thrombosis with release from adherent platelets of cell derived growth factors, along with subsequent proliferation of intimal smooth muscle cells and local infiltration of inflammatory cells contributing to vascular hyperplasia. It is important to note that multiple processes, including thrombosis, cell proliferation, cell migration and inflammation each seem to contribute to the restenotic process, and that many of these same processes contribute to the initial process of stenosis. Thus, anti-inflammatory and antiproliferative drugs, coated on stents, appear to be the most promising approach to treat various aspects of stenosis and restenosis (Hong, MK, et al., Paclitaxel-coated Gianturco-Roubin® II (GRII) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model, Coronary Artery Disease, 2001, Vol. 12, No. 6, pp. 513-515).
Numerous agents have been examined for presumed antiproliferative actions in restenosis and have shown some activity in experimental animal models. Some of the agents which have been shown to successfully reduce the extent of intimal hyperplasia in animal models include: heparin and heparin fragments (Clowes, A. and Kamovsky, M, Nature, 1977, Vol. 265, pp. 25-26), colchicine (Currier, J., et al., Circulation, 1989, Vol. 80, pp. 11-66), taxol (Sollott, S., et al., J. Clin. Invest., 1995, Vol. 95, pp. 1869-1876), cyclosporin A (Jonasson, L, et al., Proc. Natl. Acad. Sci., 1988, Vol. 85, p. 2303) and rapamycin (Marx, S., et al., Circ. Res., 1995, Vol. 76, pp. 412-417). Post-angioplasty restenosis is a multifactorial process that involves numerous interactive mechanisms. This means that effective prevention of restenosis may not be feasible with agents possessing a single mechanism of action. Accordingly, there is a need for multi-faceted approaches to the treatment and prevention of restenosis following PTCA